Methods for the administration of certain VMAT2 inhibitors

ABSTRACT

Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,1 1 b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is also being administered digoxin.

Dysregulation of dopaminergic systems is integral to several centralnervous system (CNS) disorders, including neurological and psychiatricdiseases and disorders. These neurological and psychiatric diseases anddisorders include hyperkinetic movement disorders, and conditions suchas schizophrenia and mood disorders. The transporter protein vesicularmonoamine transporter-2 (VMAT2) plays an important role in presynapticdopamine release and regulates monoamine uptake from the cytoplasm tothe synaptic vesicle for storage and release.

Despite the advances that have been made in this field, there remains aneed for new therapeutic products useful to treatment of neurologicaland psychiatric diseases and disorders and other related diseases orconditions described herein. One such agent is valbenazine, which hasthe following chemical structure:

A formulation of valbenazine:4-toluenesulfonate (1:2) (referred toherein as “valbenazine ditosyl ate”) has been previously reported in theFDA approved drug label Ingrezza®.

There is a significant, unmet need for methods for administering a VMAT2inhibitor, such as valbenazine or(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof, wherein the patient is also being treatedwith another substance which may interact with the VMAT2 inhibitor, suchas digoxin. The present disclosure fulfills these and other needs, asevident in reference to the following disclosure.

BRIEF SUMMARY

Provided is a method of administering a vesicular monoamine transport 2(VMAT2) inhibitor chosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof wherein the patient is also beingadministered digoxin, comprising: administering to the patient atherapeutically effective amount of the VMAT2 inhibitor.

Also provided is a method of administering a vesicular monoaminetransport 2 (VMAT2) inhibitor chosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof, comprising: administering to the patient atherapeutically effective amount of the VMAT2 inhibitor, subsequentlydetermining that the patient is to begin treatment with digoxin, andcontinuing administration of the therapeutically effective amount of theVMAT2 inhibitor to the patient.

Also provided is a method of administering a vesicular monoaminetransport 2 (VMAT2) inhibitor chosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof wherein the patient is also beingadministered digoxin, comprising: administering a therapeuticallyeffective amount of the VMAT2 inhibitor to the patient, wherein theadministration produces a mean digoxin C_(max) that is about 1.5 to 2.5fold higher than the mean digoxin C_(max) for a patient who isadministered digoxin alone and/or a mean digoxin AUC_(0-∞) that is about1 to about 2 fold higher than the mean digoxin AUC_(0-∞) for a patientwho is administered digoxin alone.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds, and/or compositions, and are eachhereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” or “some embodiments” or “a certain embodiment” means that aparticular feature, structure or characteristic described in connectionwith the embodiment is included in at least one embodiment. Thus, theappearances of the phrases “in one embodiment” or “in an embodiment” or“in some embodiments” or “in a certain embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Also, as used in this specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontent clearly dictates otherwise.

As used herein, “valbenazine” may be referred to as(S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester; or as L-Valine,(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ylester or as NBI-98854.

As used herein, “(+)-α-HTBZ” means the compound which is an activemetabolite of valbenazine having the structure:

(+)-α-HTBZ may be referred to as (2R, 3R, 11bR) or as (+)-α-DHTBZ or as(+)-α-HTBZ or as R,R,R-DHTBZ or as(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol;or as (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-olor as NBI-98782.

As used herein, “NBI-136110” means the compound which is a metabolite ofvalbenazine having the structure:

As used herein, “isotopic variant” means a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon 11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C) nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O),oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F), phosphorus-31(³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S),sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S),chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (123I), iodine-125 (¹²⁵I),iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). In certainembodiments, an “isotopic variant” of a compound is in a stable form,that is, non-radioactive. In certain embodiments, an “isotopic variant”of a compound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), carbon-12(¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16(¹⁶O), oxygen-17 (¹⁷O), and oxygen-18 (¹⁸O). In certain embodiments, an“isotopic variant” of a compound is in an unstable form, that is,radioactive. In certain embodiments, an “isotopic variant” of a compoundcontains unnatural proportions of one or more isotopes, including, butnot limited to, tritium (³H), carbon-11 (¹¹C), carbon-14 (¹⁴C),nitrogen-13 (¹³N), oxygen-14 (¹⁴O), and oxygen-15 (¹⁵O). It will beunderstood that, in a compound as provided herein, any hydrogen can be²H, as example, or any carbon can be ¹³C, as example, or any nitrogencan be ¹⁵N, as example, and any oxygen can be ¹⁸O, as example, wherefeasible according to the judgment of one of skill in the art. Incertain embodiments, an “isotopic variant” of a compound contains anunnatural proportion of deuterium.

With regard to the compounds provided herein, when a particular atomicposition is designated as having deuterium or “D” or “d”, it isunderstood that the abundance of deuterium at that position issubstantially greater than the natural abundance of deuterium, which isabout 0.015%. A position designated as having deuterium typically has aminimum isotopic enrichment factor of, in certain embodiments, at least1000 (15% deuterium incorporation), at least 2000 (30% deuteriumincorporation), at least 3000 (45% deuterium incorporation), at least3500 (52.5% deuterium incorporation), at least 4000 (60% deuteriumincorporation), at least 4500 (67.5% deuterium incorporation), at least5000 (75% deuterium incorporation), at least 5500 (82.5% deuteriumincorporation), at least 6000 (90% deuterium incorporation), at least6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuteriumincorporation), at least 6600 (99% deuterium incorporation), or at least6633.3 (99.5% deuterium incorporation) at each designated deuteriumposition. The isotopic enrichment of the compounds provided herein canbe determined using conventional analytical methods known to one ofordinary skill in the art, including mass spectrometry, nuclear magneticresonance spectroscopy, and crystallography.

As used herein, “hyperkinetic disorder” or “hyperkinetic movementdisorder” or “hyperkinesias” refers to disorders or diseasescharacterized by excessive, abnormal, involuntary movements. Theseneurological disorders include tremor, dystonia, myocl onus, athetosis,Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia,hemiballismus, chorea, senile chorea, or tics.

As used herein, “tardive syndrome” encompasses but is not limited totardive dyskinesia, tardive dystonia, tardive akathisia, tardive tics,myocl onus, tremor and withdrawal-emergent syndrome. Tardive dyskinesiais characterized by rapid, repetitive, stereotypic, involuntarymovements of the face, limbs, or trunk.

As used herein, “about” means±20% of the stated value, and includes morespecifically values of ±10%, ±5%, ±2% and ±1% of the stated value.

As used herein, “AUC” refers to the area under the curve, or theintegral, of the plasma concentration of an active pharmaceuticalingredient or metabolite over time following a dosing event.

As used herein “AUC_(0-t)” is the integral under the plasmaconcentration curve from time 0 (dosing) to time “t”.

As used herein, “AUG_(0-∞)” is the AUC from time 0 (dosing) to timeinfinity. Unless otherwise stated, AUC refers to AUC_(0-∞). Often a drugis packaged in a salt form, for example valbenazine ditosyl ate, and thedosage form strength refers to the mass of this salt form or theequivalent mass of the corresponding free base, valbenazine.

As used herein, C_(max) is a pharmacokinetic parameter denoting themaximum observed blood plasma concentration following delivery of anactive pharmaceutical ingredient. C_(max) occurs at the time of maximumplasma concentration, t_(max).

As used herein, “co-administer” and “co-administration” and variantsthereof mean the administration of at least two drugs to a patienteither subsequently, simultaneously, or consequently proximate in timeto one another (e.g., within the same day, or week or period of 30 days,or sufficiently proximate that each of the at least two drugs can besimultaneously detected in the blood plasma). When co-administered, twoor more active agents can be co-formulated as part of the samecomposition or administered as separate formulations. This also may bereferred to herein as “concomitant” administration or variants thereof.

As used herein, “adjusting administration”, “altering administration”,“adjusting dosing”, or “altering dosing ” are all equivalent and meantapering off, reducing or increasing the dose of the substance, ceasingto administer the substance to the patient, or substituting a differentactive agent for the substance.

As used herein, “administering to a patient” refers to the process ofintroducing a composition or dosage form into the patient via anart-recognized means of introduction.

As used herein the term “disorder” is intended to be generallysynonymous, and is used interchangeably with, the terms “disease,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms.

As used herein, a “dose” means the measured quantity of an active agentto be taken at one time by a patient. In certain embodiments, whereinthe active agent is not valbenazine free base, the quantity is the molarequivalent to the corresponding amount of valbenazine free base. Forexample, often a drug is packaged in a pharmaceutically acceptable saltform, for example valbenazine ditosyl ate, and the dosage for strengthrefers to the mass of the molar equivalent of the corresponding freebase, valbenazine. As an example, 73 mg of valbenazine tosylate is themolar equivalent of 40 mg of valbenazine free base.

As used herein, “dosing regimen” means the dose of an active agent takenat a first time by a patient and the interval (time or symptomatic) atwhich any subsequent doses of the active agent are taken by the patientsuch as from about 20 to about 160 mg once daily, e.g., about 20, about40, about 60, about 80, about 100, about 120, or about 160 mg oncedaily. The additional doses of the active agent can be different fromthe dose taken at the first time.

As used herein, “effective amount” and “therapeutically effectiveamount” of an agent, compound, drug, composition or combination is anamount which is nontoxic and effective for producing some desiredtherapeutic effect upon administration to a subject or patient (e.g., ahuman subject or patient). The precise therapeutically effective amountfor a subject may depend upon, e.g., the subject's size and health, thenature and extent of the condition, the therapeutics or combination oftherapeutics selected for administration, and other variables known tothose of skill in the art. The effective amount for a given situation isdetermined by routine experimentation and is within the judgment of theclinician.

As used herein, “informing” means referring to or providing publishedmaterial, for example, providing an active agent with published materialto a user; or presenting information orally, for example, bypresentation at a seminar, conference, or other educationalpresentation, by conversation between a pharmaceutical salesrepresentative and a medical care worker, or by conversation between amedical care worker and a patient; or demonstrating the intendedinformation to a user for the purpose of comprehension.

As used herein, “labeling” means all labels or other means of written,printed, graphic, electronic, verbal, or demonstrative communicationthat is upon a pharmaceutical product or a dosage form or accompanyingsuch pharmaceutical product or dosage form.

As used herein, “a “medical care worker” means a worker in the healthcare field who may need or utilize information regarding an activeagent, including a dosage form thereof, including information on safety,efficacy, dosing, administration, or pharmacokinetics. Examples ofmedical care workers include physicians, pharmacists, physician'sassistants, nurses, aides, caretakers (which can include family membersor guardians), emergency medical workers, and veterinarians.

As used herein, “Medication Guide” means an FDA-approved patientlabeling for a pharmaceutical product conforming to the specificationsset forth in 21 CFR 208 and other applicable regulations which containsinformation for patients on how to safely use a pharmaceutical product.A medication guide is scientifically accurate and is based on, and doesnot conflict with, the approved professional labeling for thepharmaceutical product under 21 CFR 201.57, but the language need not beidentical to the sections of approved labeling to which it corresponds.A medication guide is typically available for a pharmaceutical productwith special risk management information.

As used herein, “ patient ” or “individual” or “ subject” means amammal, including a human, for whom or which therapy is desired, andgenerally refers to the recipient of the therapy.

As used herein, “patient package insert” means information for patientson how to safely use a pharmaceutical product that is part of theFDA-approved labeling. It is an extension of the professional labelingfor a pharmaceutical product that may be distributed to a patient whenthe product is dispensed which provides consumer-oriented informationabout the product in lay language, for example it may describe benefits,risks, how to recognize risks, dosage, or administration.

As used herein, “pharmaceutically acceptable” refers to a material thatis not biologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” (or “active”) derivative or analog, refers toa derivative or analog having the same type of pharmacological activityas the parent compound and approximately equivalent in degree. The term“pharmaceutically acceptable salts” include acid addition salts whichare formed with inorganic acids such as, for example, hydrochloric orphosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropyl amine, trimethyl amine, histidine, procaine and thelike.

As used herein, a “product” or “pharmaceutical product” means a dosageform of an active agent plus published material, and optionallypackaging.

As used herein, “product insert” means the professional labeling(prescribing information) for a pharmaceutical product, a patientpackage insert for the pharmaceutical product, or a medication guide forthe pharmaceutical product.

As used herein, “professional labeling” or “prescribing information”means the official description of a pharmaceutical product approved by aregulatory agency (e.g., FDA or EMEA) regulating marketing of thepharmaceutical product, which includes a summary of the essentialscientific information needed for the safe and effective use of thedrug, such as, for example indication and usage; dosage andadministration; who should take it; adverse events (side effects);instructions for use in special populations (pregnant women, children,geriatric, etc.); safety information for the patient, and the like.

As used herein, “published material” means a medium providinginformation, including printed, audio, visual, or electronic medium, forexample a flyer, an advertisement, a product insert, printed labeling,an internet web site, an internet web page, an internet pop-up window, aradio or television broadcast, a compact disk, a DVD, an audiorecording, or other recording or electronic medium.

As used herein, “risk” means the probability or chance of adversereaction, injury, or other undesirable outcome arising from a medicaltreatment. An “acceptable risk” means a measure of the risk of harm,injury, or disease arising from a medical treatment that will betolerated by an individual or group. Whether a risk is “acceptable” willdepend upon the advantages that the individual or group perceives to beobtainable in return for taking the risk, whether they accept whateverscientific and other advice is offered about the magnitude of the risk,and numerous other factors, both political and social. An “acceptablerisk” of an adverse reaction means that an individual or a group insociety is willing to take or be subjected to the risk that the adversereaction might occur since the adverse reaction is one whose probabilityof occurrence is small, or whose consequences are so slight, or thebenefits (perceived or real) of the active agent are so great. An“unacceptable risk” of an adverse reaction means that an individual or agroup in society is unwilling to take or be subjected to the risk thatthe adverse reaction might occur upon weighing the probability ofoccurrence of the adverse reaction, the consequences of the adversereaction, and the benefits (perceived or real) of the active agent. “Atrisk” means in a state or condition marked by a high level of risk orsusceptibility. Risk assessment consists of identifying andcharacterizing the nature, frequency, and severity of the risksassociated with the use of a product.

As used herein, “safety” means the incidence or severity of adverseevents associated with administration of an active agent, includingadverse effects associated with patient-related factors (e.g., age,gender, ethnicity, race, target illness, abnormalities of renal orhepatic function, co-morbid illnesses, genetic characteristics such asmetabolic status, or environment) and active agent-related factors(e.g., dose, plasma level, duration of exposure, or concomitantmedication).

As used herein, “t_(max)” is a pharmacokinetic parameter denoting thetime to maximum blood plasma concentration following delivery of anactive pharmaceutical ingredient

As used herein, “t_(1/2)” or “plasma half-life” or “eliminationhalf-life” or the like is a pharmacokinetic parameter denoting theapparent plasma terminal phase half-life, i.e., the time, afterabsorption and distribution of a drug is complete, for the plasmaconcentration to fall by half.

As used herein, “treating” or “treatment” refers to therapeuticapplications to slow or stop progression of a disorder, prophylacticapplication to prevent development of a disorder, and/or reversal of adisorder. Reversal of a disorder differs from a therapeutic applicationwhich slows or stops a disorder in that with a method of reversing, notonly is progression of a disorder completely stopped, cellular behavioris moved to some degree, toward a normal state that would be observed inthe absence of the disorder.

As used herein, “VMAT2” refers to human vesicular monoamine transporterisoform 2, an integral membrane protein that acts to transportmonoamines, particularly neurotransmitters such as dopamine,norepinephrine, serotonin, and histamine, from cellular cytosol intosynaptic vesicles.

As used herein, the term “VMAT2 inhibitor”, “inhibit VMAT2”, or“inhibition of VMAT2” refers to the ability of a compound disclosedherein to alter the function of VMAT2. A VMAT2 inhibitor may block orreduce the activity of VMAT2 by forming a reversible or irreversiblecovalent bond between the inhibitor and VMAT2 or through formation of anoncovalently bound complex. Such inhibition may be manifest only inparticular cell types or may be contingent on a particular biologicalevent. The term “VMAT2 inhibitor”, “inhibit VMAT2”, or “inhibition ofVMAT2” also refers to altering the function of VMAT2 by decreasing theprobability that a complex forms between a VMAT2 and a naturalsubstrate.

Provided is a method of administering a vesicular monoamine transport 2(VMAT2) inhibitor chosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof wherein the patient is also beingadministered digoxin, comprising: administering to the patient atherapeutically effective amount of the VMAT2 inhibitor.

In certain embodiments, the method further comprises determining whetherthe patient is being administered digoxin. monitoring the patient forsigns and symptoms of digoxin toxicity and clinical response.

In certain embodiments, the method further comprises reducing the amountof the digoxin administered to the patient based on the patient'sability to tolerate one or more digoxin exposure-related adversereactions.

Also provided is a method of administering a vesicular monoaminetransport 2 (VMAT2) inhibitor chosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof, comprising: administering to the patient atherapeutically effective amount of the VMAT2 inhibitor, subsequentlydetermining that the patient is to begin treatment with digoxin, andcontinuing administration of the therapeutically effective amount of theVMAT2 inhibitor to the patient.

In certain embodiments, the method further comprises monitoring thepatient signs and symptoms of digoxin toxicity and clinical response.

In certain embodiments, the method further comprises reducing the amountof the digoxin administered to the patient based on the patient'sability to tolerate one or more digoxin exposure-related adversereactions.

Also provided is a method of administering a vesicular monoaminetransport 2 (VMAT2) inhibitor chosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,to a patient in need thereof wherein the patient is also beingadministered digoxin, comprising: administering a therapeuticallyeffective amount of the VMAT2 inhibitor to the patient, wherein theadministration produces a mean digoxin C_(max) that is about 1.5 to 2.5fold higher than the mean digoxin C_(max) for a patient who isadministered digoxin alone and/or a mean digoxin AUC_(0-∞) that is about1 to about 2 fold higher than the mean digoxin AUC_(0-∞) for a patientwho is administered digoxin alone.

In certain embodiments, the method further comprises informing thepatient or a medical care worker that co-administration of the VMAT2inhibitor and digoxin may result in increased digoxin exposure.

In certain embodiments, the method further comprises informing thepatient or a medical care worker that co-administration of the VMAT2inhibitor and digoxin may result in increased risk of one or moredigoxin exposure-related adverse reactions.

In certain embodiments, monitoring for signs and symptoms of digoxintoxicity and clinical response comprises monitoring the serumconcentration of the digoxin.

In certain embodiments, monitoring for signs and symptoms of digoxintoxicity and clinical response comprises determining whether the patientexperiences one or more exposure-related adverse reaction associatedwith serum digoxin concentration.

In certain embodiments, the digoxin exposure-related adverse reaction ischosen from cardiac arrhythmias and digoxin toxicity

In certain embodiments, the digoxin exposure-related adverse reaction ischosen from nausea, vomiting, abdominal pain, intestinal ischemia,hemorrhagic necrosis of the intestines, headache, weakness, dizziness,apathy, confusion, mental disturbances (such as anxiety, depression,delirium, and hallucination), and gynecomastia.

In certain embodiments, digoxin toxicity is indicated by anorexia,nausea, vomiting, visual changes and cardiac arrhythmias [first-degree,second-degree (Wenckebach), or third-degree heart block (includingasystole); atrial tachycardia with block; AV dissociation; acceleratedjunctional (nodal) rhythm; unifocal or multiform ventricular prematurecontractions (especially bigeminy or trigeminy); ventriculartachycardia; and ventricular fibrillation]. Toxicity is usuallyassociated with digoxin levels greater than 2 ng/ml although symptomsmay also occur at lower levels.

In certain embodiments, monitoring for signs and symptoms of digoxintoxicity and clinical response comprises monitoring efficacy of thedigoxin.

In certain embodiments, the method further comprises obtaining abaseline serum digoxin concentration prior to administering to thepatient the therapeutically effective amount of the VMAT2 inhibitor.

In certain embodiments, the method further comprises obtaining a serumdigoxin concentration after administering to the patient thetherapeutically effective amount of the VMAT2 inhibitor.

In certain embodiments, the method further comprises comparing thebaseline serum digoxin concentration to the serum digoxin concentrationafter administering to the patient the therapeutically effective amountof the VMAT2 inhibitor.

In certain embodiments, the dosage and/or frequency of administration ofthe digoxin is reduced.

In certain embodiments, the dosage of digoxin is decreased.

In certain embodiments, the frequency of administration of the digoxinis decreased.

In certain embodiments, the amount of digoxin being administered is10-90% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is20-80% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is30-70% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is40-60% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is 50%less than the amount that would be administered to a patient who is notalso being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered to apatient is reduced to, for example, 75% or less, 50% or less, or 25% orless of the amount that would be administered to a patient who is notalso being administered a VMAT2 inhibitor.

In certain embodiments, the VMAT2 inhibitor is administered to thepatient to treat a neurological or psychiatric disease or disorder. Incertain embodiments, the neurological or psychiatric disease or disorderis a hyperkinetic movement disorder, mood disorder, bipolar disorder,schizophrenia, schizoaffective disorder, mania in mood disorder,depression in mood disorder, treatment-refractory obsessive compulsivedisorder, neurological dysfunction associated with Lesch-Nyhan syndrome,agitation associated with Alzheimer's disease, Fragile X syndrome orFragile X-associated tremor-ataxia syndrome, autism spectrum disorder,Rett syndrome, or chorea-acanthocytosis.

In certain embodiments, the neurological or psychiatric disease ordisorder is a hyperkinetic movement disorder. In certain embodiments,the hyperkinetic movement disorder is tardive dyskinesia. In certainembodiments, the hyperkinetic movement disorder is Tourette's syndrome.In certain embodiments, the hyperkinetic movement disorder isHuntington's disease. In certain embodiments, the hyperkinetic movementdisorder is tics. In certain embodiments, the hyperkinetic movementdisorder is chorea associated with Huntington's disease. In certainembodiments, the hyperkinetic movement disorder is ataxia, chorea,dystonia, Huntington's disease, myocl onus, restless leg syndrome, ortremors.

In certain embodiments, the VMAT2 inhibitor is administered orally.

In certain embodiments, the VMAT2 inhibitor is administered in the formof a tablet or capsule.

In certain embodiments, the VMAT2 inhibitor is administered with orwithout food.

In certain embodiments, the VMAT2 inhibitor is valbenazine or apharmaceutically acceptable salt and/or isotopic variant thereof. Incertain embodiments, the VMAT2 inhibitor is valbenazine or apharmaceutically acceptable salt thereof. In certain embodiments, theVMAT2 inhibitor is a valbenazine tosylate salt. In certain embodiments,the VMAT2 inhibitor is a ditosylate salt of valbenazine.

In certain embodiments, the VMAT2 inhibitor is an isotopic variant thatis L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof.

In certain embodiments, the VMAT2 inhibitor is(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-oldihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is an isotopic variant thatis(+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-olor a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is administered in an amountequivalent to between about 20 mg and about 160 mg of valbenazine freebase. In certain embodiments, the VMAT2 inhibitor is administered in anamount equivalent to about 20 mg of valbenazine free base. In certainembodiments, the VMAT2 inhibitor is administered in an amount equivalentto about 40 mg of valbenazine free base. In certain embodiments, theVMAT2 inhibitor is administered in an amount equivalent to about 60 mgof valbenazine free base. In certain embodiments, the VMAT2 inhibitor isadministered in an amount equivalent to about 80 mg of valbenazine freebase. In certain embodiments, the VMAT2 inhibitor is administered in anamount equivalent to about 120 mg of valbenazine free base. In certainembodiments, the VMAT2 inhibitor is administered in an amount equivalentto about 160 mg of valbenazine free base.

In certain embodiments, the VMAT2 inhibitor is administered for a firstperiod of time in a first amount and then the amount is increased to asecond amount. In certain embodiments, the first period of time is aweek. In certain embodiments, the first amount is equivalent to about 40mg of valbenazine free base. In certain embodiments, the second amountis equivalent to about 80 mg of valbenazine free base.

In certain embodiments, the VMAT2 inhibitor is administered in an amountsufficient to achieve a maximal blood plasma concentration (C_(max)) of(+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and aminimal blood plasma concentration (C_(min)) of (+)-α-DHTBZ of at least15 ng per mL plasma over an 8 hour period.

In certain embodiments, the VMAT2 inhibitor is administered in an amountsufficient to achieve a maximal blood plasma concentration (C_(max)) of(+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and aminimal blood plasma concentration (Cmin) of approximately between aboutat least 33% -50% of the C_(max) over a 12 hour period.

In certain embodiments, the VMAT2 inhibitor is administered in an amountsufficient to achieve: (i) a therapeutic concentration range of about 15ng to about 60 ng of (+)-α-DHTBZ per mL plasma; and (ii) a thresholdconcentration of at least 15 ng (+)-α-DHTBZ per mL plasma over a periodof about 8 hours to about 24 hours.

In certain embodiments, the C_(max) of R,R,R-DHTBZ is about 15 ng/mL,about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL or about 60 ng/mLplasma. In certain embodiments, the C_(min) of R, R,R-DHTBZ is at least15 ng/mL, at least 20 ng/mL, at least 25 ng/mL, at least 30 ng/mL, or atleast 35 ng/mL plasma, over a period of 8 hrs, 12 hrs, 16 hrs, 20 hrs,24 hrs, 28 hrs, or 32 hrs. In certain embodiments, the C_(min) ofR,R,R-DHTBZ is between about 15 ng/mL to about 35 ng/mL.

In certain embodiments, the pharmaceutical composition is administeredin an amount sufficient to provide a C_(max) of R,R,R-DHTBZ of about 15ng/mL to about 60 ng/mL plasma and a C_(min) of approximately at least33% of the C_(max) (over a 24 hour period. In certain embodiments, thepharmaceutical composition is administered in an amount sufficient toprovide a C_(max) of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mLplasma and a C_(min) of approximately at least 50% of the C_(max) over a24 hour period. In certain embodiments, the pharmaceutical compositionis administered in an amount sufficient to provide a C_(max) ofR,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C_(min) ofapproximately between about at least 33% −50% of the C_(max) over a 24hour period.

In certain embodiments, the pharmaceutical composition is administeredin an amount sufficient to provide a C_(max) of R,R,R-DHTBZ of about 15ng/mL to about 60 ng/mL plasma and a C_(min) of approximately at least33% of the C_(max) over a 12 hour period. In certain embodiments, thepharmaceutical composition is administered in an amount sufficient toprovide a C_(max) of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mLplasma and a C_(min) of approximately at least 50% of the C_(max) over a12 hour period. In certain embodiments, the pharmaceutical compositionis administered in an amount sufficient to provide a C_(max) ofR,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C_(min) ofapproximately between about at least 33% -50% of the C_(max) over a 12hour period.

In certain embodiments, the pharmaceutical composition is administeredto a subject in an amount that provides a C_(max) of R,R,R-DHTBZ ofabout 15 ng/mL to about 60 ng/mL plasma and a C_(min) of between about 5ng/mL to about 30 ng/mL plasma over a 24 hour period. In certainembodiments, the pharmaceutical composition is administered to a subjectin an amount that provides a C_(max) of R,R,R-DHTBZ of about 15 ng/mL toabout 60 ng/mL plasma and a C_(min) of between about 7.5 ng/mL to about30 ng/mL plasma over a 24 hour period.

In certain embodiments, a method for treating neurological orpsychiatric diseases or disorders is provided herein that comprisesadministering to a subject a pharmaceutical composition comprising theVMAT2 inhibitor, as an active pharmaceutical ingredient, in an amountsufficient to provide: (i) a therapeutic concentration range of about 15ng to about 60 ng of R,R,R-DHTBZ per mL plasma; and (ii) a thresholdconcentration of at least 15 ng R,R,R-DHTBZ per mL plasma over a periodof about 8 hours to about 24 hours.

In certain embodiments, the therapeutic concentration range is about 15ng to about 35 ng, to about 40 ng, to about 45 ng, to about 50 ng, or toabout 55 ng R,R,R-DHTBZ per mL plasma.

In certain embodiments, the threshold concentration of R,R,R-DHTBZ isabout 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL orabout 60 ng/mL plasma, over a period of about 8 hrs, about 12 hrs, about16 hrs, about 20 hrs, about 24 hrs, about 28 hrs, or about 32 hrs. Incertain embodiments, the threshold concentration of R,R,R-DHTBZ isbetween about 15 ng/mL to about 35 ng/mL over a period of about 8 hoursto about 24 hours.

Plasma concentrations may be measured by methods known in the art andgenerally by tandem mass spectroscopy.

Also provided is a vesicular monoamine transport 2 (VMAT2) inhibitorchosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopicvariant thereof, for use in a method of treating a neurological orpsychiatric disease or disorder in a patient in need thereof wherein thepatient has previously been determined to have been administereddigoxin, comprising: administering to the patient a therapeuticallyeffective amount of the VMAT2 inhibitor.

Also provided is a vesicular monoamine transport 2 (VMAT2) inhibitorchosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,for use in a method of treating a neurological or psychiatric disease ordisorder in a patient in need thereof, comprising: administering to thepatient a therapeutically effective amount of the VMAT2 inhibitor,subsequently determining whether the patient is to begin treatment withdigoxin, and continuing administration of the therapeutically effectiveamount of the VMAT2 inhibitor to the patient.

Also provided is a vesicular monoamine transport 2 (VMAT2) inhibitorchosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,for use in a method of treating a neurological or psychiatric disease ordisorder in a patient in need thereof, wherein the patient haspreviously been determined to have been administered digoxin,comprising: administering to the patient a therapeutically effectiveamount of the VMAT2 inhibitor, subsequently selecting the patient thatis not able to tolerate one or more digoxin exposure-related adversereactions, and administering a reduced amount of digoxin to the patient.

Also provided is a vesicular monoamine transport 2 (VMAT2) inhibitorchosen from valbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,for use in a method of treating a neurological or psychiatric disease ordisorder in a patient in need thereof, wherein the patient haspreviously been determined to have been administered digoxin,comprising: administering to the patient a therapeutically effectiveamount of the VMAT2 inhibitor, subsequently selecting the patient thatis able to tolerate one or more digoxin exposure-related adversereactions, and continuing administering the therapeutically effectiveamount of digoxin to the patient.

Valbenazine can be prepared according to U.S. Pat. Nos. 8,039,627 and8,357,697, the disclosure of each of which is incorporated herein byreference in its entirety. Tetrabenazine may be administered by avariety of methods including the formulations disclosed in PCTPublications WO 2010/018408, WO 2011/019956, and WO 2014/047167, thedisclosure of each of which is incorporated herein by reference in itsentirety. In certain embodiments, the valbenazine for use in thecompositions and methods provided herein is in polymorphic Form I asdisclosed in U.S. Ser. No. 15/338,214, the disclosure of which isincorporated herein by reference in its entirety.

Pharmaceutical Compositions

Also provided is a composition for treating a patient in need of avesicular monoamine transport 2 (VMAT2) inhibitor chosen fromvalbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant and beingadministered digoxin, comprising: a therapeutically effective amount ofthe VMAT2 inhibitor.

In certain embodiments, the patient is monitored for signs and symptomsof digoxin toxicity and clinical response.

In certain embodiments, a reduced amount of the digoxin is administeredto the patient based on the patient's ability to tolerate one or moredigoxin exposure-related adverse reactions following administration ofthe composition comprising the therapeutically effective amount of theVMAT2 inhibitor.

Also provided is a composition for treating a patient in need of avesicular monoamine transport 2 (VMAT2) inhibitor chosen fromvalbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,comprising the VMAT2 inhibitor, characterized in that the compositioncomprising a therapeutically effective amount of the VMAT2 inhibitor isadministered to the patient subsequently determined to begin treatmentwith digoxin following administration of the composition comprising thetherapeutically effective amount of the VMAT2 inhibitor.

In certain embodiments, the patient is monitored for one or moreexposure-related adverse reactions.

In certain embodiments, a reduced amount of the VMAT2 inhibitor isadministered based on the patient's ability to tolerate one or moreexposure-related adverse reactions following administration of thecomposition comprising a therapeutically effective amount of the VMAT2inhibitor or the composition comprising a reduced amount of the VMAT2inhibitor.

Also provided is a composition for treating a patient in need of avesicular monoamine transport 2 (VMAT2) inhibitor chosen fromvalbenazine and(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof,and being treated with digoxin, comprising: a therapeutically effectiveamount of the VMAT2 inhibitor, wherein administration of the compositionproduces a mean digoxin C_(max) that is about 1.5 to 2.5 fold higherthan the mean digoxin C_(max) for a patient who is administered digoxinalone and/or a mean digoxin AUC_(0-∞) that is about 1 to about 2 foldhigher than the mean digoxin AUC_(0-∞) for a patient who is administereddigoxin alone.

In certain embodiments, the patient or a medical care worker is informedthat co-administration of the VMAT2 composition and digoxin may resultin increased digoxin exposure.

In certain embodiments, the patient or a medical care worker is informedthat co-administration of the VMAT2 composition and digoxin may resultin increased risk of one or more digoxin exposure-related adversereactions.

In certain embodiments, the serum concentration of digoxin is monitored.

In certain embodiments, the dosage and/or frequency of administration ofthe digoxin is reduced. In certain embodiments, the dosage of digoxin isdecreased. In certain embodiments, the frequency of administration ofthe digoxin is decreased.

In certain embodiments, the composition is for treating a neurologicalor psychiatric disease or disorder.

In certain embodiments, the composition is administered orally.

In certain embodiments, the composition is administered in the form of atablet or capsule.

In certain embodiments, the composition is administered with or withoutfood.

In certain embodiments, the VMAT2 inhibitor is valbenazine or apharmaceutically acceptable salt and/or isotopic variant thereof. Incertain embodiments, the VMAT2 inhibitor is valbenazine or apharmaceutically acceptable salt thereof. In certain embodiments, theVMAT2 inhibitor is a valbenazine tosylate salt. In certain embodiments,the VMAT2 inhibitor is a ditosylate salt of valbenazine.

In certain embodiments, is an isotopic variant that is L-Valine,(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ylester or a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol,or a pharmaceutically acceptable salt and/or isotopic variant thereof.In certain embodiments, the VMAT2 inhibitor is(+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-oldihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is an isotopic variant thatis(+)-α-3-isobutyl-9,10-di(methoxy-d₃)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-olor a pharmaceutically acceptable salt thereof.

In certain embodiments, the composition is administered in an amountequivalent to between about 20 mg and about 160 mg of valbenazine freebase. In certain embodiments, the composition is administered in anamount equivalent to about 20 mg of valbenazine free base. In certainembodiments, the composition is administered in an amount equivalent toabout 40 mg of valbenazine free base. In certain embodiments, thecomposition is administered in an amount equivalent to about 60 mg ofvalbenazine free base. In certain embodiments, the composition isadministered in an amount equivalent to about 80 mg of valbenazine freebase. In certain embodiments, the composition is administered in anamount equivalent to about 120 mg of valbenazine free base. In certainembodiments, the composition is administered in an amount equivalent toabout 160 mg of valbenazine free base.

In certain embodiments, the composition is administered for a firstperiod of time in a first amount and then the amount of the VMAT2inhibitor is increased to a second amount of the VMAT2 inhibitor. Incertain embodiments, the first period of time is a week. In certainembodiments, the first amount is equivalent to about 40 mg ofvalbenazine free base. In certain embodiments, the second amount isequivalent to about 80 mg of valbenazine free base.

In certain embodiments, the composition is administered in an amountsufficient to achieve a maximal blood plasma concentration (C_(max)) of(+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and aminimal blood plasma concentration (C_(min)) of (+)-α-DHTBZ of at least15 ng per mL plasma over an 8 hour period.

In certain embodiments, the composition is administered in an amountsufficient to achieve a maximal blood plasma concentration (C_(max)) of(+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and aminimal blood plasma concentration (C_(min)) of approximately betweenabout at least 33%-50% of the C_(max) over a 12 hour period.

In certain embodiments, the composition is administered in an amountsufficient to achieve: (i) a therapeutic concentration range of about 15ng to about 60 ng of (+)-α-DHTBZ per mL plasma; and (ii) a thresholdconcentration of at least 15 ng (+)-α-DHTBZ per mL plasma over a periodof about 8 hours to about 24 hours.

In certain embodiments, the amount of digoxin being administered is10-90% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is20-80% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is30-70% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is40-60% less than the amount that would be administered to a patient whois not also being administered a VMAT2 inhibitor.

In certain embodiments, the amount of digoxin being administered is 50%less than the amount that would be administered to a patient who is notalso being administered a VMAT2 inhibitor.

Also provided herein is a pharmaceutical composition for use in treatingneurological or psychiatric diseases or disorders, comprising the VMAT2inhibitor as an active pharmaceutical ingredient, in combination withone or more pharmaceutically acceptable carriers or excipients.

The choice of excipient, to a large extent, depends on factors, such asthe particular mode of administration, the effect of the excipient onthe solubility and stability of the active ingredient, and the nature ofthe dosage form.

The pharmaceutical compositions provided herein may be provided in unitdosage forms or multiple-dosage forms. Unit-dosage forms, as usedherein, refer to physically discrete units suitable for administrationto human and animal subjects and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of the activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of unit-dosage forms include ampoules, syringes, andindividually packaged tablets and capsules. Unit dosage forms may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofmultiple-dosage forms include vials, bottles of tablets or capsules, orbottles of pints or gallons.

The pharmaceutical compositions provided herein may be administeredalone, or in combination with one or more other compounds providedherein, one or more other active ingredients. The pharmaceuticalcompositions provided herein may be formulated in various dosage formsfor oral, parenteral, and topical administration. The pharmaceuticalcompositions may also be formulated as a modified release dosage form,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art). The pharmaceutical compositions provided herein may beadministered at once, or multiple times at intervals of time. It isunderstood that the precise dosage and duration of treatment may varywith the age, weight, and condition of the patient being treated, andmay be determined empirically using known testing protocols or byextrapolation from in vivo or in vitro test or diagnostic data. It isfurther understood that for any particular individual, specific dosageregimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the formulations.

Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions may contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVTCEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch,and mixtures thereof. The binder or filler may be present from about 50to about 99% by weight in the pharmaceutical compositions providedherein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Vee gum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, com oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL®200 (W. R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant. Suitable glidants include colloidal silicon dioxide,CAB-0-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc.Coloring agents include any of the approved, certified, water solubleFD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate,and color lakes and mixtures thereof. A color lake is the combination byadsorption of a water-soluble dye to a hydrous oxide of a heavy metal,resulting in an insoluble form of the dye. Flavoring agents includenatural flavors extracted from plants, such as fruits, and syntheticblends of compounds which produce a pleasant taste sensation, such aspeppermint and methyl salicylate. Sweetening agents include sucrose,lactose, mannitol, syrups, glycerin, and artificial sweeteners, such assaccharin and aspartame. Suitable emulsifying agents include gelatin,acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylenesorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80(TWEEN® 80), and triethanolamine oleate. Suspending and dispersingagents include sodium carboxymethylcellulose, pectin, tragacanth,Veegum, acacia, sodium carbomethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrolidone. Preservatives includeglycerin, methyl and propylparaben, benzoic add, sodium benzoate andalcohol. Wetting agents include propylene glycol monostearate, sorbitanmonooleate, diethylene glycol monolaurate, and polyoxyethylene laurylether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.Examples of non-aqueous liquids utilized in emulsions include mineraloil and cottonseed oil. Organic acids include citric and tartaric acid.Sources of carbon dioxide include sodium bicarbonate and sodiumcarbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation. The pharmaceuticalcompositions provided herein may be provided as compressed tablets,tablet triturates, chewable lozenges, rapidly dissolving tablets,multiple compressed tablets, or enteric-coating tablets, sugar-coated,or film-coated tablets. Enteric coated tablets are compressed tabletscoated with substances that resist the action of stomach acid butdissolve or disintegrate in the intestine, thus protecting the activeingredients from the acidic environment of the stomach. Enteric-coatingsinclude, but are not limited to, fatty acids, fats, phenylsalicylate,waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.Sugar-coated tablets are compressed tablets surrounded by a sugarcoating, which may be beneficial in covering up objectionable tastes orodors and in protecting the tablets from oxidation. Film-coated tabletsare compressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. The capsules may also be coated as known bythose of skill in the art in order to modify or sustain dissolution ofthe active ingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term“lower” means an alkyl having between 1 and 6 carbon atoms), e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or polyalkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems.

The pharmaceutical compositions provided herein may be provided asnoneffervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.Coloring and flavoring agents can be used in all of the above dosageforms. The pharmaceutical compositions provided herein may be formulatedas immediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction, such as antacids, proton pump inhibitors, and H₂-receptorantagonists.

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

Parenteral Administration

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science.

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl phydroxybenzates, thimerosal, benzalkonium chloride,benzethonium chloride, methyl- and propylparabens, and sorbic acid.Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin,hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, andsulfobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In certain embodiments, the pharmaceutical compositions are provided asready-to-use sterile solutions. In certain embodiments, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In certain embodiments, thepharmaceutical compositions are provided as ready-to-use sterilesuspensions. In certain embodiments, the pharmaceutical compositions areprovided as sterile dry insoluble products to be reconstituted with avehicle prior to use. In certain embodiments, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In certain embodiments, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

Topical Administration

The pharmaceutical compositions provided herein may be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, include (intra)dermal, conjuctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,uretheral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryopretectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon bases, including such as lard, benzoinatedlard, olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption bases, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable bases,such as hydrophilic ointment; water-soluble ointment bases, includingpolyethylene glycols of varying molecular weight; emulsion bases, eitherwater-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, includingcetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Thesevehicles are emollient but generally require addition of antioxidantsand preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include vehicles, such asstiffening agents, which produce a melting point in the proximity ofbody temperature, when formulated with the pharmaceutical compositionsprovided herein; and antioxidants as described herein, includingbisulfite and sodium metabisulfite. Suitable vehicles include, but arenot limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax,and appropriate mixtures of mono-, di- and triglycerides of fatty acids,hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate,polyacrylic acid; glycerinated gelatin. Combinations of the variousvehicles may be used. Rectal and vaginal suppositories may be preparedby the compressed method or molding. The typical weight of a rectal andvaginal suppository is about 2 to 3 g.

The pharmaceutical compositions provided herein may be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein, a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein may be micronized to asize suitable for delivery by inhalation, such as 50 micrometers orless, or 10 micrometers or less. Particles of such sizes may be preparedusing a comminuting method known to those skilled in the art, such asspiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as/−leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients include dextran, glucose,maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Thepharmaceutical compositions provided herein for inhaled/intranasaladministration may further comprise a suitable flavor, such as mentholand levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

Modified Release

The pharmaceutical compositions provided herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile- orpulsed-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms.

The pharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art.

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acidglycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinylchloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethyleneterephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, and;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate,;and fatty compounds, such as camauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents waterswellable hydrophilic polymers,which are also referred to as “osmopolymers” and “hydrogels,” including,but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol,; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-tolunesulfonic acid, succinic acid, and tartaric acid; urea; andmixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MannogemeEZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CAethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water, as disclosed in U.S.Pat. No. 5,798,119. Such hydrophobic but water-permeable membrane aretypically composed of hydrophobic polymers such as polyalkenes,polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acidderivatives, polyethers, polysulfones, polyethersulfones, polystyrenes,polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers,natural waxes, and synthetic waxes. The delivery port(s) on thesemipermeable membrane may be formed postcoating by mechanical or laserdrilling. Delivery port(s) may also be formed in situ by erosion of aplug of water-soluble material or by rupture of a thinner portion of themembrane over an indentation in the core. In addition, delivery portsmay be formed during coating process.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients asdescribed herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients.

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 pm to about 3 mm, about 50 pm to about2.5 mm, or from about 100 pm to 1 mm in diameter. Such multiparticulatesmay be made by the processes know to those skilled in the art, includingwet-and dry-granulation, extrusion/spheronization, roller-compaction,melt-congealing, and by spray-coating seed cores.

Other excipients as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various filmformingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

Targeted Delivery

The pharmaceutical compositions provided herein may also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems.

Dosages

In the treatment, prevention, or amelioration of one or more symptoms oftic disorders or other conditions, disorders or diseases associated withVMAT2 inhibition, an appropriate dosage level generally is about 0.001to 100 mg per kg patient body weight per day (mg/kg per day), about 0.01to about 80 mg/kg per day, about 0.1 to about 50 mg/kg per day, about0.5 to about 25 mg/kg per day, or about 1 to about 20 mg/kg per day,which may be administered in single or multiple doses. Within this rangethe dosage may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0, 1 to 15, 1to 20, or 1 to 50 mg/kg per day. In certain embodiments, the dosagelevel is about 0.001 to 100 mg/kg per day.

In certain embodiments, the dosage level is about from 25 to 100 mg/kgper day. In certain embodiments, the dosage level is about 0.01 to about40 mg/kg per day. In certain embodiments, the dosage level is about 0.1to about 80 mg/kg per day. In certain embodiments, the dosage level isabout 0.1 to about 50 mg/kg per day. In certain embodiments, the dosagelevel is about 0.1 to about 40 mg/kg per day. In certain embodiments,the dosage level is about 0.5 to about 80 mg/kg per day. In certainembodiments, the dosage level is about 0.5 to about 40 mg/kg per day. Incertain embodiments, the dosage level is about 0.5 to about 25 mg/kg perday. In certain embodiments, the dosage level is about 1 to about 80mg/kg per day. In certain embodiments, the dosage level is about 1 toabout 75 mg/kg per day. In certain embodiments, the dosage level isabout 1 to about 50 mg/kg per day. In certain embodiments, the dosagelevel is about 1 to about 40 mg/kg per day. In certain embodiments, thedosage level is about 1 to about 25 mg/kg per day.

In certain embodiments, the dosage level is about from 5.0 to 150 mg perday, and in certain embodiments from 10 to 100 mg per day. In certainembodiments, the dosage level is about 80 mg per day. In certainembodiments, the dosage level is about 40 mg per day.

For oral administration, the pharmaceutical compositions can be providedin the form of tablets containing 1.0 to 1,000 mg of the activeingredient, particularly about 1, about 5, about 10, about 15, about 20,about 25, about 30, about 40, about 45, about 50, about 75, about 80,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. In certain embodiments, the pharmaceuticalcompositions can be provided in the form of tablets containing about 100mg of the active ingredient. In certain embodiments, the pharmaceuticalcompositions can be provided in the form of tablets containing about 80mg of the active ingredient. In certain embodiments, the pharmaceuticalcompositions can be provided in the form of tablets containing about 75mg of the active ingredient. In certain embodiments, the pharmaceuticalcompositions can be provided in the form of tablets containing about 50mg of the active ingredient. In certain embodiments, the pharmaceuticalcompositions can be provided in the form of tablets containing about 40mg of the active ingredient. In certain embodiments, the pharmaceuticalcompositions can be provided in the form of tablets containing about 25mg of the active ingredient. The compositions may be administered on aregimen of 1 to 4 times per day, including once, twice, three times, andfour times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds provided herein may also be combined or used incombination with other agents useful in the treatment, prevention, oramelioration of one or more symptoms of the diseases or conditions forwhich the compounds provided herein are useful, including tic disordersand other conditions commonly treated with antipsychotic medication.

In certain embodiments, the compounds provided herein may also becombined or used in combination with a typical antipsychotic drug. Incertain embodiments, the typical antipsychotic drug is fluphenazine,haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride,thioridazine, or trifluoperazine. In certain embodiments, theantipsychotic drug is an atypical antipsychotic drug. In certainembodiments, the atypical antipsychotic drug is aripiprazole, asenapine,clozapine, iloperidone, olanzapine, paliperidone, quetiapine,risperidone, or ziprasidone. In certain embodiments, the atypicalantipsychotic drug is clozapine.

Such other agents, or drugs, may be administered, by a route and in anamount commonly used thereof, simultaneously or sequentially with thecompounds provided herein. When compounds provided herein are usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compoundsprovided herein may be utilized, but is not required. Accordingly, thepharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to the compounds provided herein.

The weight ratio of the compounds provided herein to the second activeingredient may be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when the compounds provided herein are used incombination with the second drug, or a pharmaceutical compositioncontaining such other drug, the weight ratio of the particulates to thesecond drug may range from about 1,000:1 to about 1:1,000, or about200:1 to about 1:200.

Combinations of the particulates provided herein and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

Examples of embodiments of the present disclosure are provided in thefollowing examples. The following examples are presented only by way ofillustration and to assist one of ordinary skill in using thedisclosure. The examples are not intended in any way to otherwise limitthe scope of the disclosure.

EXAMPLES Example 1

A Phase 1, Open-Label, One-Sequence Crossover Study to Assess the Effectof N131-98854 on the Pharmacokinetics of Digoxin in Healthy Subjects

This was a Phase 1, open-label, one-sequence crossover, drug-interactionstudy of NBI-98854 in a total of 24 healthy adult subjects (12 males and12 females). At screening, subjects were genotyped to determine theircytochrome P450 2D6 (CYP2D6) status. Subjects who were poor metabolizerswere excluded from study participation. After providing informedconsent, subjects were screened for eligibility to participate in thestudy within 28 days before Day 1 (the first day of study drugadministration). Subjects who met the eligibility criteria were admittedto the study center on the morning of Day −1 (the day before dosing) andremained at the study center until the end of the study (Day 17).Subjects received digoxin 0.5 mg (administered as two 0.25 mg immediaterelease [IR] tablets) once daily on Days 1 and 14 at approximately 0800hours. In addition, subjects received NBI-98854 80 mg once daily(administered as two 40 mg capsules) on Days 10 through 16 atapproximately 0800 hours. On Day 14, digoxin was administered at thesame time as the NBI-98854 dose.

Subjects were required to fast overnight from midnight until 4 hourspostdose on Days 1 and 14. Additionally, clinical laboratory assessmentswere performed under fasted conditions. On each dosing day, study drugwas administered with 240 mL of water. Subjects were given standardmeals upon completion of study assessments/dosing at regular meal timesduring their stay in the study center. Subjects were discharged from thestudy center on Day 17 (final study day or upon early termination) afterall safety evaluations and study assessments were completed.

Blood samples were collected for PK analyses of NBI-98854 and itsmetabolites, NBI-98782 and NBI-136110, and for digoxin at scheduledtimes during the study. Safety was assessed throughout the study.

NBI-98854 40 mg capsules were administered orally. The dose of NBI-98854was based on the ditosylate salt (dose expressed as free base). Subjectsreceived a single dose of NBI-98854 80 mg (as two 40 mg capsules) twiceduring the study on Days 10 through 16 at approximately 0800 hours.

Pharmacokinetics

Blood samples to determine digoxin plasma concentrations were collectedon Days 1 and 14 at approximately 30 minutes before digoxin dosing, and15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48,60, and 72 hours after digoxin dosing.

The following PK parameters were assessed for digoxin:

-   -   Area under the plasma concentration versus time curve from 0 to        24 hours (AUC₀₋₂₄)    -   Area under the plasma concentration versus time curve from 0 to        4 hours (AUC₀₋₄)    -   Area under the plasma concentration versus time curve from 0        hours to last measurable concentration (AUC_(0-tlast))    -   Area under the plasma concentration versus time curve from 0        hours extrapolated to infinity (AUC_(0-∞))    -   Maximum plasma concentration (C_(max))    -   Time to maximum plasma concentration (t_(max))    -   Time prior to the first measurable concentration (T_(lag))    -   Apparent terminal half-life (t_(1/2)).

Blood samples to determine plasma concentrations of NBI-98854 and itsmetabolites, NBI-98782 and NBI-136110, were collected on Days 10 to 13at approximately 30 minutes before NBI-98854 dosing; on Day 14 atapproximately 30 minutes before NBI-98854 dosing, and at 30 minutes, and1, 2, 4, 8, and 12 hours after NBI-98854 dosing; on Days 15 and 16 atapproximately 30 minutes before NBI-98854 dosing; and on Day 17 (or uponearly termination) at approximately 24 hours after the Day 16 NBI-98854dose before discharge. The following plasma PK parameters were assessedfor NBI-98854, NBI-98782, and NBI-136110: AUC₀₋₂₄, C_(max), and t_(max).

During the review of PK data, 3 subjects (Subjects 1011008, 1011016, and1011018) were identified with unusually low NBI-98854, NBI-98782, andNBI-136110 plasma concentrations on Day 14 after receiving the fifthdose of NBI-98854, coadministered with digoxin. As a result, both peakand total exposures (Cmax and AUC₀₋₂₄) of all 3 analytes wereconsiderably lower than the expected ranges and the mean values observedon Day 14 (excluding these 3 subjects). These low values wereinconsistent with drug concentrations that would be expected after dailyadministration of NBI-98854. Expected concentrations of NBI-98854 on Day14 are represented by the C_(max) and AUC₀₋₂₄ values excluding the 3outliers. Because the objective of the study was to evaluate NBI-98854as a Pgp inhibitor at its steady state exposure, and the Day 14 data forthese 3 subjects appeared to be anomalous, PK data were also analyzedexcluding the data from these 3 subjects. This analysis is referred toas the PK analysis subset in this report. The results of this PKanalysis subset are presented in this section and provide a moreconservative estimation of drug interaction between digoxin andNBI-98854.

Subjects with Low C_(max) and AUC₀₋₂₄ on Day 14 C_(max) (ng/mL) AUC₀₋₂₄(ng × hr/mL) Age Genotype NBI- NBI- NBI- NBI- NBI- NBI- Subject (yr)/SexClassification 98854 98782 136110 98854 98782 136110 1011008 36/FExtensive 11.8 9.61 7.15 146 155 105 1011016 38/M Intermediate 34.1 11.022.8 450 175 370 1011018 41/M Intermediate 30.0 9.02 25.6 393 135 400Mean (SD) Values (Excluding Subjects 916 39.4 124 6150 695 1910 (220)(12.9) (30.0) (1510) (227) (459)

PK parameters for digoxin alone and digoxin in combination withNBI-98854 are summarized below (excluding Subjects 1011008, 1011016, and1011018).

Digoxin was readily absorbed after oral administration alone or incombination with NBI-98854. Mean digoxin C_(max) and AUC_(-∞)) wereapproximately 1.9-fold and 1.4-fold higher, respectively, when digoxinwas administered in combination with NBI-98854 than after treatment withdigoxin alone. Median digoxin t_(max) was 0.25 hours shorter (0.75 hoursvs. 1.0 hours) after administration with digoxin in combination withNBI-98854 than after administration with digoxin alone. Mean digoxin finwas similar with and without NBI-98854 administration (35 and 36 hours,respectively).

The PK data for t_(max), T_(lag), t_(1/2), MRT, and Vz/F were rounded to2 significant figures and all other parameters (AUC₀₋₂₄, AUC_(0-tlast),AUC_(0-∞), C_(max), and CL/F) were rounded to 3 significant figures. Thelast significant figure was rounded up if the digit to the right of itwas ≥5, and was rounded down if the digit to the right of it was ≤4.

Summary of Pharmacokinetic Parameters for Digoxin Alone Versus Digoxinin Combination with NBI-98854 (PK Analysis Subset) Digoxin Digoxin (0.5mg) + Parameter (0.5 mg) NBI-98854 (80 mg) Statistic (N = 17) (N = 17)AUC₀₋₂₄ (ngxhr/mL) 13.5 (3.54) 18.8 (3.06) Mean (SD) 26.9 17.2 GeometricCV (%) AUC₀₋₄ (ngxhr/mL) 5.27 (1.44) 8.18 (1.46) Mean (SD) 28.4 18.7Geometric CV (%) AUC_(0-tlast) (ngxhr/mL) 23.4 (6.36) 31.8 (5.35) Mean(SD) 28.3 17.5 Geometric CV (%) AUC_(0-∞)(ngxhr/mL) 30.9 (9.25) 41.0(7.38) Mean (SD) 30.9 18.2 Geometric CV (%) C_(max) (ng/mL) 2.47 (0.989)4.61 (1.47) Mean (SD) 42.6 35.4 Geometric CV (%) t_(max) (hr) 1.0 (0.75,2.0) 0.75 (0.50, 1.5) Median (min, max) T_(lag) (hr) 0.015 (0.061) 0Mean (SD) t_(1/2) (hr) 36 (7.4) 35 (7.2) Mean (SD) 21 21 Geometric CV(%) Data exclude Subjects 1011008, 1011016, and 1011018. The PK data fort_(max), T_(lag), and t_(1/2) were rounded to 2 significant figures andall other parameters (AUC₀₋₄, AUC₀₋₂₄, AUC_(0-tlast), AUC_(0-∞) andC_(max)) were rounded to 3 significant figures. The last significantfigure was rounded up if the digit to the right of it was >5, and wasrounded down if the digit to the right of it was <4.

The digoxin geometric mean ratios and associated 90% CIs for AUC_(0-∞),AUC_(0-tlast), and C_(max) after treatment with digoxin in combinationwith NBI-98854 or digoxin alone are summarized below. Geometric meanratios for AUC_(0-∞), AUC_(0-tlast), and C_(max) after treatment withdigoxin in combination with NBI-98854 or digoxin alone were 136.4%,138.5%, and 191.7%, respectively. The corresponding upper and lower 90%CI bounds for AUC_(0-∞) (126.0% to 147.6%), AUC_(0-tlast) (127.0% to151.1%), and C_(max) (166.4% to 220.8%) were outside the ‘no effect’range of 80% to 125%, indicating an effect of treatment with NBI-98854on digoxin AUC_(0-∞), AUC_(0-tlast), and C_(max).

Digoxin Geometric Mean Ratios for Pharmacokinetic Exposure Parameters(PK Analysis Subset) Ratio^(a) (%) 90% (Digoxin + NBI- ConfidenceParameter 98854 vs. Digoxin Interval^(b) AUC_(0-∞) (ngxhr/mL) 136.4126.0, 147.6 AUC_(0-tlast) (ngxhr/mL) 138.5 127.0, 151.1 C_(max) (ng/mL)191.7 166.4, 220.8 ^(a)Ratio of geometric least-squares means was basedon a mixed model using log-transformed (base 10) data. ^(b)The 90%confidence interval for geometric mean ratio was based on least-squaresmeans using log-transformed (base 10) data. Note: Data exclude Subjects1011008, 1011016, and 1011018.

PK data for NBI-98854, NBI-98782, and NBI-136110 were summarized for thesafety analysis set (excluding the 3 subjects). PK parameters forNBI-98854, NBI-98782, and NBI-136110 are summarized below. NBI-98854 wasreadily absorbed after oral administration of NBI-98854.

Summary of Pharmacokinetic Parameters for NBI- 98854, NBI-98782, andNBI-136110 Relative to the Day 14 Dose (Safety Analysis Set) NBI-9885480 mg NBI- Parameter NBI-98854 NBI-98782 136110 Statistic N = 21^(a) N =21^(a) N = 21^(a) AUC₀₋₂₄ (ngxhr/mL) n = 17 n = 17 n = 17 Mean (SD) 6150(1510) 695 (227) 1910 (459)  Geometric CV (%) 28.3 36.4 27.8 C_(max)(ng/mL) n = 17 n = 17 n = 17 Mean (SD) 916 (220) 39.4 (12.9)  124 (30.0)Geometric CV (%) 28.4 35.9 27.9 t_(max) (hr) n = 17 n = 17 n = 17 Median(min. max) 1.0 4.0 4.0 (0.50, 2.0) (4.0, 8.0) (1.0, 4.0) Data reflectsubjects in the safety analysis set with Day 14 PK parameters foranalytes, excluding Subjects 1011008, 1011016, and 1011018.

The results of this study showed that NB1-98854 80 mg coadministeredwith 0.5 mg digoxin resulted in an approximate 1.9-fold increase in theC_(max) of digoxin. The effect of NBI-98854 on digoxin AUC_(0-∞) wasmodest (1.4-fold increase) and the mean t_(1/2) of digoxin was similarwith and without NBI-98854 administration. The 90% CI for the geometricmean ratios (166.4% to 220.8% for C_(max) and 126.0% to 147.6% forAUC_(0-∞)) were outside the ‘no effect’ range of 80% to 125%, indicatingan effect of treatment with NBI-98854 on digoxin C_(max) and AUC_(0-∞).Therefore, these data are consistent with inhibition of the efflux pumpPgp by NBI-98854 in the gut, which results in increased absorption ofdigoxin.

The present study was designed to evaluate the PK of digoxin whenadministered alone and concomitantly with NBI-98854 and the safety andtolerability of NB1-98854 when administered alone and concomitantly withdigoxin.

NBI-98854 was found to be a weak inhibitor of the efflux transporterPgp. Based on a comparison of the potency of Pgp inhibition (IC₅₀ of23.8 pM) and the systemic plasma concentrations of NBI-98854 (observedsteady state of C_(max) of NBI-98854 after an 80 mg dose of 916 ng/mL or2.19 pM in the present study [molecular weight of NBI-98854 is 418.578g/mol]), a systemic interaction with the transporter was unlikely.However, the concentrations of NBT-98854 in the gastrointestinal tractcould be much higher. Therefore, the possibility existed that NBI-98854could alter digoxin PK by inhibiting the gut Pgp.

The results of this study showed that NBI-98854 80 mg coadministeredwith 0.5 mg digoxin resulted in an approximate 1.9-fold increase in theC_(max) of digoxin. The effect of NBI-98854 on digoxin AUC_(0-∞) wasmodest (1.4-fold increase) and the tin of digoxin was similar with andwithout NB1-98854 administration. Therefore, these data are consistentwith inhibition of the efflux pump Pgp by NBI-98854 in the gut, whichresults in increased absorption of digoxin.

Based on a review of all study records, the unusually low NBI-98854,NBI-98782, and NB1-136110 plasma concentrations observed in Subjects1011008, 1011016, and 1011018 were likely due to subject noncompliance.Exposure measures of NBI-98854 and its metabolites, NBI-98782, andNBI-136110, on Day 14 (excluding the 3 subjects) were generallyconsistent with previous studies.

Safety

Safety was assessed based on adverse events (AEs), clinical laboratorytests, vital signs, physical examinations, and electrocardiograms(ECGs).

Safety Results

No pre-treatment AEs occurred in the study. TEAEs were assigned to atreatment based on the time of the last treatment administered prior tothe AE onset.

There were no deaths or SAEs reported in this study. AEs leading todiscontinuation from the study were reported in 3 subjects (one due toinsomnia and anxiety, one due to anxiety and nausea, and one due toanxiety). Overall, 20 subjects (83.3%) experienced an AE during thestudy. By treatment group, AEs were experienced by 41.7% (10 subjects)of subjects after treatment with digoxin (until subjects receivedNBI-98854 on Day 10), by 65.2% of subjects after starting NBI-98854 onDay 10 (until subjects received both study drugs on Day 14), and by65.0% of subjects after concomitant administration of digoxin andNBI-98854 on Day 14.

Somnolence and anxiety were the most common AEs reported afteradministration of NBI-98854 alone, reported by 39.1% (9 subjects) and17.4% (4 subjects) of subjects, respectively, and considered by theinvestigator to be possibly or definitely related to study drug.Diarrhea was the most common AE after concomitant administration ofdigoxin and NBI-98854, reported in 20.0% (4 subjects) of subjects andwas considered by the investigator to be not related to study drug.Headache was also common; occurring after digoxin administration alone(20.8%; 5 subjects) and after administration of digoxin and NBI-98854(15.0%; 3 subjects). The majority of AEs were considered mild tomoderate in intensity. The number and percentage of subjects whoexperienced TEAEs are summarized by treatment below.

Treatment-Emergent Adverse Events Reported in >1 Subject in AnyTreatment Group (Safety Analysis Set) Digoxin NBI-98854 Digoxin (0.5mg) + (0.5 mg)^(a) (80 mg)^(b) NBI-98854 (80 Overall N = 24 N = 23 N =20 (N = 24) Preferred Term n (%) n (%) n (%) n (%) Overall 10 (41.7) 15(65.2) 13 (65.0) 20 (83.3) Somnolence 0  9 (39.1) 0  9 (37.5) Headache 5 (20.8) 1 (4.3)  3 (15.0)  7 (29.2) Anxiety 0  4 (17.4) 1 (5.0)  5(20.8) Insomnia 0 2 (8.7)  3 (15.0)  4 (16.7) Diarrhea 0 0  4 (20.0)  4(16.7) Restlessness 0 1 (4.3)  2 (10.0)  3 (12.5) Abnormal 0 0  3 (15.0) 3 (12.5) dreams ^(a)Onset on or after the first dose of digoxin (Day 1)but prior to the first dose of NBI-98854 (Day 10). ^(b)Onset on or afterthe first dose of NBI-98854 (Day 10) but prior to the Day 14 dose ofdigoxin and NBI-98854. ^(c)Onset on or after the Day 14 dose of digoxinand NBI-98854.

Three subjects experienced AEs leading to discontinuation from thestudy. These AEs included anxiety, insomnia, and nausea. The most commonAE reported for study discontinuation was anxiety, reported in all 3subjects. One event of anxiety was considered severe.

Conclusions

Concomitant administration of digoxin and NBI-98854 results in increasedabsorption of digoxin, which is consistent with inhibition of the effluxpump P-glycoprotein (Pgp) by NBI-98854 in the gut.

Concomitant administration of digoxin and NBI-98854 led to anapproximate 1.9-fold increase in C_(max) and an approximate 1.4-foldincrease in AUC_(0-∞) of digoxin compared with administration of digoxinalone. The 90% CI for the geometric mean ratios (166.4% to 220.8% forC_(max) and 126.0% to 147.6% for AUC_(0-∞)) were outside the ‘no effect’range of 80% to 125%, indicating an effect of treatment with NBI-98854on digoxin C_(max) and AUC_(0-∞). Mean digoxin t>/₂ was similar with andwithout NBT-98854 administration (35 and 36 hours, respectively). Mediandigoxin t_(max) was 0.25 hours shorter (0.75 hours vs. 1.0 hours) afteradministration of digoxin in combination with NBI-98854 than afteradministration of digoxin alone.

NBI-98854 80 mg was well tolerated in healthy subjects when administeredalone or concomitantly with digoxin. No deaths or serious adverse events(SAEs) were reported in this study. AEs leading to discontinuation fromthe study were reported in 3 subjects (one due to insomnia and anxiety,one due to anxiety and nausea, and one due to anxiety). The most commonAEs were somnolence (9 subjects, 39.1%) and anxiety (4 subjects; 17.4%)after beginning NBI-98854 administration, and were considered by theinvestigator to be possibly or definitely related to study drug.Diarrhea was the most common AE after concomitant administration ofdigoxin and NBI-98854 (4 subjects; 20.0%) and was considered by theinvestigator to be not related to study drug. The majority of AEs wereconsidered mild to moderate in intensity. There were no clinicallysignificant changes in clinical laboratory test results, vital signs,physical examinations, or ECG parameters during the study. No subjecthad a corrected QT interval using Fridericia's formula (QTcF)interval >450 msec or a maximum increase from baseline >30 msec.

Example 2 Pharmacologic Characterization of Valbenazine, Tetrabenazine,and Metabolite Thereof

Upon oral administration, TBZ is reduced to form four discrete isomericsecondary alcohol metabolites, collectively referred to asdihydrotetrabenazine (DHTBZ), which contains three asymmetric carboncenters (C-2, C-3, and C-11β), which could hypothetically result ineight stereoisomers. However, because the C-3 and C-11β carbons havefixed relative configurations, only four stereoisomers are possible:(R,R,R-DHTBZ or (+)-α-DHTBZ (alternate nomenclature) or NBI-98782(laboratory nomenclature); S,S,S-DHTBZ or (−)-α-DHTBZ or NBI-98771;S,R,R-DHTBZ or (+)-β-DHTBZ or NBI-98795; and R,S,S-DHTBZ or (−)-β-DHTBZor NBI-98772.

The affinity of each compound was measured by inhibition of [³H]-DHTBZbinding to rat forebrain membranes. The affinities relative toR,R,R-DHTBZ were also calculated and are presented. Data are reported asboth the negative logarithm of the Ki (pKi) for statistical calculationwith the normally distributed binding parameter used to determine themean and SEM. The Ki value was determined from the mean pKi as 10(-pKi).The R,R,R-DHTBZ stereoisomer binds with the highest affinity to both ratand human VMAT2 (Ki=1.0 to 4.2 nM). In comparison, the remaining threeDHTBZ stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, R,S,S-DHTBZ) bind toVMAT2 with a Ki values of 9.7, 250, and 690 nM, respectively.

In Vitro VMAT2 Binding Affinity in Rat Forebrain VMAT2 Affinity pK_(i)mean Relative to Compound K_(i),, nm (SEM) N R,R,R-DHTBZ^(a) R,R,R-DHTBZ4.2 8.38 (0.42) 27 1.0 S,R,R-DHTBZ 9.7 8.01 (0.32) 6 2.3 S,S,S-DHTBZ 2506.60 (0.22) 4 60 R,S,S-DHTBZ 690 6.16 (0.05) 5 160 ^(a)Affinity relativeto R,R,R-DHTBZ was calculated using the K_(i) value determined in thesame study

The primary metabolic clearance pathways of valbenazine (VBZ, NBI-98854)are hydrolysis (to form R,R,R-DHTBZ) and mono-oxidation (to form themetabolite NBI-136110). R,R,R-DHTBZ and NBI-136110, the two mostabundant circulating metabolites of VBZ, are formed gradually and theirplasma concentrations decline with half-lives similar to VBZ.

VBZ and its metabolites, R,R,R-DHTBZ and NBI-136110, were tested fortheir ability to inhibit the binding of [3H]-DHTBZ to VMAT2 in celllines or native tissues. The affinity of each compound was measured byinhibition of [³H]-DHTBZ binding to either human platelets or ratstriatal membranes. The affinities relative to R,R,R-DHTBZ were alsocalculated and are presented. Data are reported as both the negativelogarithm of the K_(i) (pKi) for statistical calculation with thenormally distributed binding parameter used to determine the mean andSEM (n=4 for each compound in each tissue). The K_(i) value wasdetermined from the mean pKi as 10^((−pKi)). The primary metaboliteR,R,R-DHTBZ, was the most potent inhibitor of VMAT2 in rat striatum andhuman platelet homogenates.

In Vitro VMAT2 Binding Affinity of Valbenazine and its Metabolites RatStriatum Human Platelets Affinity Affinity pKi Relative pKi Relativemean to R,R,R- mean to R,R,R- Compound Ki, nm (SEM) DHTBZ Ki, nm (SEM)DHTBZ Valbenazine 110 6.95 39 150 6.82 45 (0.02) (0.02) R,R,R- 1.98 8.701.0 3.1 8.52 1.0 DHTBZ (0.09) (0.03) NBI-136610 160 6.80 57 220 6.65 67(0.02) (0.04)

VBZ and NBI-136110 had similar effects on VMAT2 inhibition, but with Kivalues that were approximately 40-65 times the Ki values (loweraffinity) of R,R,R-DHTBZ. These results were corroborated by theradioligand binding assay of DHTBZ stereoisomers (i.e., TBZ metabolites)in the rat forebrain, which also showed R,R,R-DHTBZ to be the mostpotent inhibitor of VMAT2, followed by S,R,R-DHTBZ. Comparatively,S,S,S-DHTBZ and R,S,S-DHTBZ, the other two primary metabolites of TBZ,were found to be poor VMAT2 inhibitors with affinities approximately 60and 160 times weaker than R,R,R-DHTBZ.

The affinity of VBZ and its metabolites R,R,R-DHTBZ and NBI-136110 forother targets beyond VMAT2 was assessed in an extensive Cerep screen ofmultiple classes of protein targets including GPCRs, cell-surfacemonoamine transporters, and ion channels including the cardiac potassiumchannel, human ether-à-go-go-related gene (HERG).

The multi-target activity screen of more than 80 targets for thesecompounds (Cerep screen) demonstrated that VBZ and its metabolites,R,R,R-DHTBZ and NBI-136110, did not inhibit the binding of cognateligands to any of the targets by more than 50% at concentrations of 1-10μM. In contrast, the other three DHTBZ stereoisomers (S,R,R-DHTBZ, S, S,S-DHTBZ, R,S,S-DHTBZ), which are metabolites of TBZ but not VBZ,demonstrated >50% inhibition of ligand binding to a number of receptorsubtypes including serotonin, dopamine and adrenergic receptors. Resultsexpressed as percent of control specific binding: (tested compoundspecific binding/control specific binding)×100. All compounds weretested at 1 or 10 μM final concentration and results are an excerpt of alarger 80 target panel performed as an initial screen at Cerep (n=2 foreach compound at each target). Bolded results (>50%) indicate activityat target receptor.

In vitro activity of valbenazine and DHTBZ stereoisomers at dopamine,serotonin, and adrenergic receptors Receptor R,R,R- S,R,R- S,S,S-DHTBZ/Target Valbenazine DHTBZ DHTBZ R,S,S-DHTBZ^(a) Serotonin5- 26 17 69 96HT_(1A) Serotonin5- 1 −4 3 84 HT_(2A) Serotonin5- 4 3 80 98 HT₇ Dopamine8 −6 −5 82 D₁ Dopamine 2 6 25 89 D_(2(s)) ^(a)For purposes of the broadpanel screen, the S,S,S- and R,S,S-metabolites were tested as a 50/50mixture.

To describe the monoamine systems in greater detail, detailedradioligand binding assays were performed for dopamine, serotonin andadrenergic receptor subtypes as well as the transporters for dopamine(DAT), serotonin (SERT), and norepinephrine (NET) for the commonmetabolite of TBZ and VBZ (R,R,R-DHTBZ) and the other relevantmetabolites unique to TBZ and VBZ. This detailed analysis revealed thehigh specificity of R,R,R-DHTBZ for the VMAT2 transporter and thenon-specific activities of the other TBZ metabolites, includingrelatively high affinity for dopamine and serotonin receptor subtypes.Interestingly, the R,R,R-DHTBZ metabolite showed the greatestnon-selectivity with respect to the monoamine receptors. None of the TBZor VBZ metabolites had any affinity for the monoamine transporters DAT,SERT or NET. To complete the selectivity profile for VMAT2, thefunctional activity for the human VMAT1 transporter of these compoundswas tested in cells expressing VMAT1. While the non-selectiveirreversible high-affinity uptake inhibitor of VMAT1, reserpine,substantially inhibited uptake through VMAT1, there was no significantinhibitory activity of TBZ, VBZ, or its metabolites R,R,R-DHTBZ orNBI-136110 at concentrations up to 10 μM. For both VMAT1 and VMAT2,uptake was measured in the untransfected host cells and was found to besimilar to transfected cells in the presence of excess reserpine.

Radioligand binding assays and the broad panel screen indicate that inaddition to varying potency at the VMAT2 transporter, two of the otherDHTBZ metabolites of TBZ (S,S,S-DHTBZ and R,S,S-DHTBZ) interact with D1and D2 receptors. Since VBZ is not metabolized to either of these DHTBZstereoisomers, its effects on postsynaptic dopamine receptors eitherdirectly or indirectly through the metabolites are non-existent.

Moreover, results from the broad panel screen indicate that VBZ and itsmajor metabolites (R,R,R-DHTBZ and NBI-136110) have little to noaffinity for more than 80 binding sites, including receptors, monoaminetransporters, and ion channels. This profile suggests a low potentialfor off-target pharmacological effects. In addition, uptake studiesusing TBZ, VBZ and its metabolites, R,R,R-DHTBZ and NBI-136110,confirmed the selectivity of these compounds for VMAT2 as they had nosignificant effect on the uptake of monoamines through VMAT1 compared toreserpine, a known VMAT1/VMAT2 inhibitor.

The selectivity and specificity of VBZ was distinctively demonstratedusing two in vivo surrogate measures of pharmacological effects. Ptosis,known to occur via adrenergic activation and prolactin release from thepituitary, modulated through the D2 dopamine receptor, demonstrated thedifference between treatment with TBZ and VBZ. TBZ, VBZ and R,R,R-DHTBZinduced ptosis in an equivalent manner. This confirms that themetabolites formed by dosing TBZ or VBZ, or dosing of the activemetabolite itself (R,R,R-DHTBZ) all have activity at VMAT2 affectingpresynaptic monoamine release, in this case, related to norepinephrinerelease specifically to induce ptosis. Following similar treatment, butthis time using prolactin release as a surrogate for dopaminergicmodulation, R,R,R-DHTBZ and VBZ (to a lesser extent) induced a similarincrease in serum prolactin levels as TBZ.

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

The invention claimed is:
 1. A method for treating a patient with ahyperkinetic movement disorder, wherein the hyperkinetic movementdisorder is chorea associated with Huntington's disease, and wherein thepatient is also being co-administered digoxin, comprising: a. orallyadministering to the patient a therapeutically effective amount of avesicular monoamine transporter 2 (VMAT2) inhibitor chosen from(S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylester and pharmaceutically acceptable salts thereof; b. monitoring thedigoxin concentration in the patient's blood; and c. reducing the doseof digoxin when the digoxin exposure in the patient's blood is increasedas compared with the digoxin level in a patient who is administereddigoxin alone.
 2. The method of claim 1, wherein the digoxin exposure ismeasured as the area under the plasma concentration versus time curvefrom 0 hours extrapolated to infinity or measured as the maximumobserved blood plasma concentration (C_(max)) at the time of maximumplasma concentration (t_(max)).
 3. The method of claim 1, wherein theincreased digoxin exposure increases the risk of one or moreexposure-related adverse reactions.
 4. The method of claim 1, furthercomprising monitoring the patient for one or more exposure-relatedadverse reactions.
 5. The method of claim 4, wherein the one or moreexposure-related adverse reactions is selected from headache, anxiety,insomnia, diarrhea, restlessness, and abnormal dreams.
 6. The method ofclaim 1, further comprising obtaining a baseline serum digoxinconcentration prior to administering to the patient the therapeuticallyeffective amount of the VMAT2 inhibitor.
 7. The method of claim 1,wherein the VMAT2 inhibitor is administered in the form of a tablet orcapsule.
 8. The method of claim 1, wherein the VMAT2 inhibitor is apharmaceutically acceptable salt of (S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]H-pyrido[2,1a]isoquinolin-2-ylester.
 9. The method of claim 1, wherein the VMAT2 inhibitor is aditosylate salt of (S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylester.
 10. The method of claim 1, wherein the therapeutically effectiveamount is an amount equivalent to about 40 mg as measured by(S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily for one week, and anamount equivalent to about 80 mg as measured by(S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylester once daily after one week.
 11. The method of claim 1, wherein thetherapeutically effective amount is an amount equivalent to betweenabout 20 mg to about 160 mg as measured by (S)-2-amino-3-methyl-butyricacid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylester once daily.
 12. The method of claim 1, wherein the therapeuticallyeffective amount is an amount equivalent to about 40 mg as measured by(S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily.
 13. The method ofclaim 1, wherein the therapeutically effective amount is an amountequivalent to about 60 mg as measured by (S)-2-amino-3-methyl-butyricacid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily.
 14. The method ofclaim 1, wherein the therapeutically effective amount is an amountequivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyricacid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily.
 15. The method ofclaim 1, wherein the co-administration of the VMAT2 inhibitor withdigoxin increases digoxin levels because of inhibition of intestinalP-glycoprotein (P-gp) by the VMAT2 inhibitor.